Aim: Circulating levels of glucocorticoids display diurnal fluctuations, and are known to act as an internal synchronizer (or zeitgeber) of many peripheral tissues. Interestingly, the primary glucocorticoid in mice, corticosterone (CORT), is known to influence brown adipose tissue (BAT) activity. In this study, we explored whether the circadian rhythm of CORT determines rhythmic BAT activity and metabolic health in mice.

Methods & Results: In male C57Bl/6J mice, we found that the rhythmicity in plasma CORT levels closely coincides with the rhythmic activity of BAT, i.e. highest uptake of fatty acids for combustion at the start of the wakeful period. To investigate the causality of this relationship, mice were subcutaneously implanted with pellets releasing a continuous low dose of CORT, resulting in flattened circulating CORT levels (i.e. similar morning and evening levels intermediate to those found normally at the circadian peak). Strikingly, flattened CORT rhythm was accompanied by a loss of circadian rhythm in BAT activity as assessed by triglyceride-derived fatty acid uptake. To determine whether flattened CORT rhythm, and thereby BAT rhythm, results in metabolic disease, we investigated the effect of low dose CORT pellets in APOE*3-Leiden.CETP mice as a model for hyperlipidemia and metabolic syndrome. After 5 weeks of intervention, flattened CORT increased fat mass (+2.8 g, P<0.05), and induced lipid accumulation in white adipose tissue (+65%, P<0.01) and BAT (+43%, P<0.05), which was accompanied by delayed plasma clearance and reduced uptake of fatty acids by BAT (-51%, P<0.001).

Conclusion: Collectively, these results indicate that CORT rhythmicity dictates BAT activity, and that disturbance of this rhythm decreases BAT activity and adversely affects metabolic health. As many individuals use synthetic glucocorticoids, which affects the normal glucocorticoid rhythm, this justifies further research on the interplay between glucocorticoids, BAT rhythm, and metabolic health in humans.